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The following is a summary of “Mechanism of antithrombin deficiency due to the novel variant C32W in the C-terminus of the signal peptide,” published in the February 2025 issue of the International Journal of Hematology by Kikuchi et al.
A novel SERPINC1 variant, c.96 T>G, p.Cys32Trp (C32W), was identified at the signal peptide cleavage site in a patient with congenital antithrombin (AT) deficiency. Its impact on AT trafficking and secretion remains unknown.
Researchers conducted a retrospective study to analyze the intracellular dynamics and signal peptide cleavage of the C32W variant of the AT (AT-C32W) variant.
They transfected Wild-type AT (AT-WT) and AT-C32W expression vectors into HEK293 cells. They performed functional analyses using western blotting and proteasome inhibition experiments. They evaluated signal peptide cleavage by peptide sequencing.
The results showed AT-C32W antigen levels were 3.8% in cell lysates and 4.8% in culture supernatants. Proteasome inhibition increased AT-C32W to 71.5% of AT-WT. Peptide sequencing identified an N-terminal fragment of the signal peptide only in AT-C32W.
Investigators found that the AT-C32W signal peptide was improperly cleaved, leading to intracellular degradation by proteasomes and type I AT deficiency. Further studies were needed to clarify the mechanisms of such variants.
Source: link.springer.com/article/10.1007/s12185-025-03945-x
